Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant hereditary cancer syndrome caused by a germline inactivating mutation in one of the alleles of the gene encoding the tricarboxylic acid (TCA) cycle enzyme, fumarate hydratase (FH). HLRCC patients are predisposed to develop aggressive papillary renal cell carcinoma type 2 (PRCC2) at an early age. The cancer tissues exhibit a loss-of- heterozygosity at the FH locus, indicating biallelic FH inactivation (FH-/-) as a critical event in tumorigenesis. These tumors often metastasize early, limiting the effectiveness of surgical intervention. Moreover, the tumors are resistant to all known chemo, targeted, and radio therapies, making PRCC2 a major cause of death among HLRCC patients. Therefore, a treatment strategy against HLRCC is urgently needed. FH-/- imparts very specific changes to the cancer cells. Particularly, FH-/- cancer cells accumulate high level of the TCA cycle intermediate, fumarate, which alters cellular signaling in very specific ways. Identifying these FH- /- specific cellular changes will therefore offer ways to target the FH-/- cancer cells, while sparing normal cell. This application exploits a FH-/--specific vulnerability that we discovered recently. Specifically, FH-/- alters cellular iron signaling, making the cells sensitive to an iron dependent cell death mechanism known as ferroptosis. We hypothesized that ferritin inhibition in FH-/- cancer cells will further enhance their sensitivity to ferroptosis while concurrently inhibiting the ferritin-dependent pro-proliferative signaling. We will test our hypothesis through the following aims: (1) Define and compare pathway alterations induced by different methods of ferritin inhibition in FH-/- cancer cells. (2) Evaluate the efficacy of combining ferritin inhibition with ferroptosis inducing compounds (FINS) in vitro and confirm their mechanisms of action. (3) Validate the efficacy of combining ferritin inhibition with FINS in vivo. Insights gained from this study will positively impact the treatment of other ferroptosis sensitive tumors.